Syntax-like Structures in Maternal Contact Calls of Chestnut-Crowned Babblers (Pomatostomus ruficeps).

The combination of meaning-bearing units (e.g., words) into higher-order structures (e.g., compound words and phrases) is integral to human language. Despite this central role of syntax in language, little is known about its evolutionary progression. Comparative data using animal communication systems offer potential insights, but only a handful of species have been identified to combine meaningful calls together into larger signals. We investigated a candidate for syntax-like structure in the highly social chestnut-crowned babbler (Pomatostomus ruficeps). Using a combination of behavioral observations, acoustic analyses, and playback experiments, we test whether the form and function of maternal contact calls is modified by combining the core "piping" elements of such calls with at least one other call element or call. Results from the acoustic analyses (236 analysed calls from 10 individuals) suggested that piping call elements can be flexibly initiated with either "peow" elements from middle-distance contact calls or adult "begging" calls to form "peow-pipe" and "beg-pipe" calls. Behavioral responses to playbacks (20 trials to 7 groups) of natural peow-pipe and beg-pipe calls were comparable to those of artificially generated versions of each call using peow elements and begging calls from other contexts. Furthermore, responses to playbacks (34 trials to 7 groups) of the three forms of maternal contact calls (piping alone, peow-pipe, beg-pipe) differed. Together these data suggest that meaning encoded in piping calls is modified by combining such calls with begging calls or peow elements used in other contexts and so provide rare empirical evidence for syntactic-like structuring in a nonhuman animal.

Clutch Size, but Not Egg Volume, Increases with Rainfall in an Arid-dwelling Bird.

Understanding how animals maximize reproductive success in variable environments is important in determining how populations will respond to increasingly extreme weather events predicted in the face of changing climates. Although temperature is generally considered a key factor in reproductive decisions, rainfall is also an important predictor of prey availability in arid environments. Here, we test the impact of weather (i.e., rainfall and temperature) on female reproductive investment in an arid-dwelling bird (i.e., clutch size and egg volume) and tradeoffs between the two. We predicted that female chestnut-crowned babblers (Pomatostomus ruficeps), endemic to the arid region of Australia, would increase clutch size at the expense of egg volume in response to variation in rainfall and temperature. We found that over 14 breeding seasons, clutch size decreased with increasing temperature, but increased following more rain. Egg volume, on the other hand, became larger as temperatures increased and, although not related to the amount of rain, was related to the number of days since the last rainfall. Finally, egg size decreased as clutch size increased, indicating a tradeoff between the two reproductive parameters. Our results suggest that chestnut-crowned babblers breed reactively in response to variable environments. We expect that clutch size variation in response to rain may reflect the impact of rain on arthropod abundance, whereas the effect of temperature may represent an established decline in clutch size observed in other seasonal breeders. As the tradeoff between clutch size and egg volume was modest, and clutch sizes were modified to a greater extent than egg volumes in response to rainfall, we suggest selection is more likely to increase offspring number than quality, at least in favorable years. Our results support the idea that reproductive investment is variable in fluctuating environments, which has implications for species living in habitats experiencing more extreme and less predictable weather as the global climate changes.

Does surgical volume correlate with outcomes in TMJ replacement surgery?

OBJECTIVE: To survey oral and maxillofacial surgeons (OMS) who perform temporomandibular joint replacement (TMJR) to determine whether length of surgery, specific TMJR protocols, or the incidence of complications are related to experience and case volume. STUDY DESIGN: An anonymous electronic survey was emailed to 407 surgeon members of the American Association of Oral and Maxillofacial Surgeons, American Society of Temporomandibular Joint Surgeons, and European Society of Temporomandibular Joint Surgeons known to have TMJR experience via publications or reputation. The descriptive survey contained multiple choice and open-ended questions. Descriptive statistics were computed for each variable for data analysis. RESULTS: Forty-nine surgeons completed the survey. The average stock TMJR cases included 54.6% unilateral and 50.5% bilateral cases. The average custom TMJR cases included 50.5% unilateral and 49.5% bilateral cases. Average procedure time for stock TMJR was 2.86 hours for unilateral, and 5.30 hours for bilateral cases. The average procedure time for a custom TMJR was 2.75 hours for unilateral, and 4.87 hours for bilateral cases. Average duration of hospital stay for stock and custom TMJR cases was 1.49 and 1.41 days (unilateral), and 1.98 and 1.95 days (bilateral). CONCLUSIONS: This study provides some pilot data that demonstrates that the length of surgery, specific TMJR surgical protocols, and the incidence of complications may be related to surgeon TMJR experience and case volume.

Practice-Oriented Research: An Introduction to New Developments and Future Directions.

Aimed at understanding and improving psychological therapies as they are conducted in clinical routine, practice-oriented research (POR) is now a well-established approach to the scientific foundations of mental health care services. Resting on the accumulation of a wide range of practice-based evidence related to treatment outcome and process, as well as factors associated with the participants of psychotherapy and its context, POR is ripe for new developments - regarding what to investigate and how to investigate it. This paper is the introduction of a series devoted to recent advances and future directions of POR as their pertained to routine outcome monitoring, technologies and artificial intelligence, the integration of constructs and methods from program evaluation and implementation science, and the investigation of populations with limited financial resources across various regions of the world. The series also includes commentaries from two leaders of POR.

DeepFLAIR: A neural network approach to mitigate signal and contrast loss in temporal lobes at 7 Tesla FLAIR images.

BACKGROUND AND PURPOSE: Higher magnetic field strength introduces stronger magnetic field inhomogeneities in the brain, especially within temporal lobes, leading to image artifacts. Particularly, T2-weighted fluid-attenuated inversion recovery (FLAIR) images can be affected by these artifacts. Here, we aimed to improve the FLAIR image quality in temporal lobe regions through image processing of multiple contrast images via machine learning using a neural network. METHODS: Thirteen drug-resistant MR-negative epilepsy patients (age 29.2 ± 9.4y, 5 females) were scanned on a 7 T MRI scanner. Magnetization-prepared (MP2RAGE) and saturation-prepared with 2 rapid gradient echoes, multi-echo gradient echo with four echo times, and the FLAIR sequence were acquired. A voxel-wise neural network was trained on extratemporal-lobe voxels from the acquired structural scans to generate a new FLAIR-like image (i.e., deepFLAIR) with reduced temporal lobe inhomogeneities. The deepFLAIR was evaluated in temporal lobes through signal-to-noise (SNR), contrast-to-noise (CNR) ratio, the sharpness of the gray-white matter boundary and joint-histogram analysis. Saliency mapping demonstrated the importance of each input image per voxel. RESULTS: SNR and CNR in both gray and white matter were significantly increased (p < 0.05) in the deepFLAIR's temporal ROIs, compared to the FLAIR. The gray-white matter boundary sharpness was either preserved or improved in 10/13 right-sided temporal regions and was found significantly increased in the ROIs. Multiple image contrasts were influential for the deepFLAIR reconstruction with the MP2RAGE second inversion image being the most important. CONCLUSIONS: The deepFLAIR network showed promise to restore the FLAIR signal and reduce contrast attenuation in temporal lobe areas. This may yield a valuable tool, especially when artifact-free FLAIR images are not available.

Selective concentration of iron, titanium, and zirconium substrate minerals within Gregory's diverticulum, an organ unique to derived sand dollars (Echinoidea: Scutelliformes).

Gregory's diverticulum, a digestive tract structure unique to a derived group of sand dollars (Echinoidea: Scutelliformes), is filled with sand grains obtained from the substrate the animals inhabit. The simple methods of shining a bright light through a specimen or testing response to a magnet can reveal the presence of a mineral-filled diverticulum. Heavy minerals with a specific gravity of >2.9 g/cm3 are selectively concentrated inside the organ, usually at concentrations one order of magnitude, or more, greater than found in the substrate. Analyses of diverticulum content for thirteen species from nine genera, using optical mineralogy, powder X-ray diffraction, scanning electron microscopy and energy dispersive X-ray spectroscopy, as well as micro-computed tomography shows the preference for selection of five major heavy minerals: magnetite (Fe3O4), hematite (Fe2O3), ilmenite (FeTiO3), rutile (TiO2), and zircon (ZrSiO4). Minor amounts of heavy or marginally heavy amphibole, pyroxene and garnet mineral grains may also be incorporated. In general, the animals exhibit a preference for mineral grains with a specific gravity of >4.0 g/cm3, although the choice is opportunistic and the actual mix of mineral species depends on the mineral composition of the substrate. The animals also select for grain size, with mineral grains generally in the range of 50 to 150 µm, and do not appear to alter this preference during ontogeny. A comparison of analytical methods demonstrates that X-ray attenuation measured using micro-computed tomography is a reliable non-destructive method for heavy mineral quantification when supported by associated analyses of mineral grains extracted destructively from specimens or from substrate collected together with the specimens. Commonalities in the electro-chemical surface properties of the ingested minerals suggest that such characteristics play an important role in the selection process.

Alloplastic TMJ replacement in the skeletally immature patient - A systematic review.

This study assessed the current evidence for the use of TMJR reconstruction in skeletally immature patients. A systematic review was conducted according to PRISMA guidelines. An electronic search in PubMed and Embase was performed. Meta-analysis randomized controlled trials (RCTs), cohort studies, observational studies, case series, and case reports were eligible for inclusion. Case reports were also included due to the limited number of publications identified with the predefined terms. Exclusion criteria were: (1) studies written in a language other than English; (2) full-text unavailability (i.e., posters and conference abstracts). The selected studies were assessed for risk of bias. A meta-analysis was not performed as it necessitates a substantial between-study design homogeneity; hence, a descriptive synthesis of data was performed. There were 9 TMJR device reconstruction studies involving 14 subjects 13 years of age or younger. Follow-up ranged from 7 months to 120 months. All papers reported significant decrease in pain and improvement of diet. All prostheses were functional. No material failures of the prosthesis components were observed. The mandible continued to show limited growth following TMJR and most of the cases required no secondary or revision surgery even when the patient reached skeletal maturity. This systematic review had some limitations. The studies included had a low level of evidence and a high risk of bias. Most of the studies had a small patient sample, and no study had a control group. The literature reviewed supports the use of TMJR devices in the restoration of mandibular function and form in skeletally immature patients.

Drug-Polymer Nanodroplet Formation and Morphology Drive Solubility Enhancement of GDC-0810.

Nanodroplet formation is important to achieve supersaturation of active pharmaceutical ingredients (APIs) in an amorphous solid dispersion. The aim of the current study was to explore how polymer composition, architecture, molar mass, and surfactant concentration affect polymer-drug nanodroplet morphology with the breast cancer API, GDC-0810. The impact of nanodroplet size and morphology on dissolution efficacy and drug loading capacity was explored using polarized light microscopy, dynamic light scattering, and cryogenic transmission electron microscopy. Poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) (PND) was synthesized as two linear derivatives and two bottlebrush derivatives with carboxylated or PEGylated end-groups. Hydroxypropyl methylcellulose acetate succinate grade MF (HPMCAS-MF) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) were included as commercial polymer controls. We report the first copolymerization synthesis of a PVPVA bottlebrush copolymer, which was the highest performing excipient in this study, maintaining 688 µg/mL GDC-0810 concentration at 60 wt % drug loading. This is likely due to strong polymer-drug noncovalent interactions and the compaction of GDC-0810 along the PVPVA bottlebrush backbone. Overall, it was observed that the most effective formulations had a hydrodynamic radius less than 25 nm with tightly compacted nanodroplet morphologies.

Surgical complications of vagus nerve stimulation surgery: A 14-years single-center experience.

Introduction: Vagus nerve stimulation (VNS) is the most frequently used neuromodulation treatment for Drug-Resistant Epilepsy (DRE) patients. Complications of VNS surgery include surgical site infection and unilateral vocal cord paresis. Complication rates vary across studies. Research question: What is the safety profile of VNS related surgeries? Materials and methods: Retrospective cohort study using patient files of DRE-patients who had undergone primary implantation of a VNS-system, replacement of the VNS pulse generator, replacement of the lead, replacement of both pulse generator and lead, or VNS removal surgery in the Maastricht UMC+. Multiple Imputation was used for missing data. Univariable and multivariable logistic regression analysis were performed to analyze possible risk factors, in case of a small sample size, an independent-samples t-test and Fisher's exact test or Pearson's X2-test were used. The complication rate was calculated as percentage. Results: This study included a total of 606 VNS surgical procedures, leading to 67 complications of which 3 permanent complications. Complication rate after primary implantation was 13.4%; 2,5% for pulse generator replacement; 21.4% for lead revision and 27.3% for complete VNS removal. No statistically significant results were found when analyzing the results of adults and children <18 years separately. Discussion and conclusion: Complication rates of VNS-related surgeries in our own institutional series are low and comparable to previously reported series. VNS surgery is a relatively safe procedure. The complication rate differs per type of surgery and mean surgery duration was longer for patients with complications after lead revision surgery compared to patients without complications.

Predator selection on multicomponent warning signals in an aposematic moth.

Aposematic prey advertise their unprofitability with conspicuous warning signals that are often composed of multiple color patterns. Many species show intraspecific variation in these patterns even though selection is expected to favor invariable warning signals that enhance predator learning. However, if predators acquire avoidance to specific signal components, this might relax selection on other aposematic traits and explain variability. Here, we investigated this idea in the aposematic moth Amata nigriceps that has conspicuous black and orange coloration. The size of the orange spots in the wings is highly variable between individuals, whereas the number and width of orange abdominal stripes remains consistent. We produced artificial moths that varied in the proportion of orange in the wings or the presence of abdominal stripes. We presented these to a natural avian predator, the noisy miner (Manorina melanocephala), and recorded how different warning signal components influenced their attack decisions. When moth models had orange stripes on the abdomen, birds did not discriminate between different wing signals. However, when the stripes on the abdomen were removed, birds chose the model with smaller wing spots. In addition, we found that birds were more likely to attack moths with a smaller number of abdominal stripes. Together, our results suggest that bird predators primarily pay attention to the abdominal stripes of A. nigriceps, and this could relax selection on wing coloration. Our study highlights the importance of considering individual warning signal components if we are to understand how predation shapes selection on prey warning coloration.

Theoretical relationships between axoneme distortion and internal forces and torques in ciliary beating.

The axoneme is an intricate nanomachine responsible for generating the propulsive oscillations of cilia and flagella in an astonishing variety of organisms. New imaging techniques based on cryoelectron-tomography (cryo-ET) and subtomogram averaging have revealed the detailed structures of the axoneme and its components with sub-nm resolution, but the mechanical function of each component and how the assembly generates oscillations remains stubbornly unclear. Most explanations of oscillatory behavior rely on the dynamic regulation of dynein by some signal, but this may not be necessary if the system of dynein-driven slender filaments is dynamically unstable. Understanding the possibility of instability-driven oscillations requires a multifilament model of the axoneme that accounts for distortions of the axoneme as it bends. Active bending requires forces and bending moments that will tend to change the spacing and alignment of doublets. We hypothesize that components of the axoneme resist and respond to these loads in ways that are critical to beating. Specifically, we propose (i) that radial spokes provide torsional stiffness by resisting misalignment (as well as spacing) between the central pair and outer doublets, and (ii) that the kinematics of dynein arms affect the relationships between active forces and bending moments on deforming doublets. These proposed relationships enhance the ability of theoretical, multifilament models of axonemal beating to generate propulsive oscillatory waveforms via dynamic mechanical instability.

Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.

The goal of precision medicine is to utilize our knowledge of the molecular causes of disease to better diagnose and treat patients. However, there is a substantial mismatch between the small number of food and drug administration (FDA)-approved drugs and annotated coding variants compared to the needs of precision medicine. This review introduces the concept of physics-based precision medicine, a scalable framework that promises to improve our understanding of sequence-function relationships and accelerate drug discovery. We show that accounting for the ensemble of structures a protein adopts in solution with computer simulations overcomes many of the limitations imposed by assuming a single protein structure. We highlight studies of protein dynamics and recent methods for the analysis of structural ensembles. These studies demonstrate that differences in conformational distributions predict functional differences within protein families and between variants. Thanks to new computational tools that are providing unprecedented access to protein structural ensembles, this insight may enable accurate predictions of variant pathogenicity for entire libraries of variants. We further show that explicitly accounting for protein ensembles, with methods like alchemical free energy calculations or docking to Markov state models, can uncover novel lead compounds. To conclude, we demonstrate that cryptic pockets, or cavities absent in experimental structures, provide an avenue to target proteins that are currently considered undruggable. Taken together, our review provides a roadmap for the field of protein science to accelerate precision medicine.

Empirical Analysis of Drug Targets for Nervous System Disorders.

The discovery and development of drugs to treat diseases of the nervous system remains challenging. There is a higher attrition rate in the clinical stage for nervous system experimental drugs compared to other disease areas. In the preclinical stage, additional challenges arise from the considerable effort required to find molecules that penetrate the blood-brain barrier (BBB) coupled with the poor predictive value of many preclinical models of nervous system diseases. In the era of target-based drug discovery, the critical first step of drug discovery projects is the selection of a therapeutic target which is largely driven by its presumed pathogenic involvement. For nervous system diseases, however, the feasibility of identifying potent molecules within the stringent range of molecular properties necessary for BBB penetration should represent another important factor in target selection. To address the latter, the present review analyzes the distribution of human protein targets of FDA-approved drugs for nervous system disorders and compares it with drugs for other disease areas. We observed a substantial difference in the distribution of therapeutic targets across the two clusters. We expanded on this finding by analyzing the physicochemical properties of nervous and non-nervous system drugs in each target class by using the central nervous system multiparameter optimization (CNS MPO) algorithm. These data may serve as useful guidance in making more informed decisions when selecting therapeutic targets for nervous system disorders.

PopShift: A Thermodynamically Sound Approach to Estimate Binding Free Energies by Accounting for Ligand-Induced Population Shifts from a Ligand-Free Markov State Model.

Obtaining accurate binding free energies from in silico screens has been a long-standing goal for the computational chemistry community. However, accuracy and computational cost are at odds with one another, limiting the utility of methods that perform this type of calculation. Many methods achieve massive scale by explicitly or implicitly assuming that the target protein adopts a single structure, or undergoes limited fluctuations around that structure, to minimize computational cost. Others simulate each protein-ligand complex of interest, accepting lower throughput in exchange for better predictions of binding affinities. Here, we present the PopShift framework for accounting for the ensemble of structures a protein adopts and their relative probabilities. Protein degrees of freedom are enumerated once, and then arbitrarily many molecules can be screened against this ensemble. Specifically, we use Markov state models (MSMs) as a compressed representation of a protein's thermodynamic ensemble. We start with a ligand-free MSM and then calculate how addition of a ligand shifts the populations of each protein conformational state based on the strength of the interaction between that protein conformation and the ligand. In this work we use docking to estimate the affinity between a given protein structure and ligand, but any estimator of binding affinities could be used in the PopShift framework. We test PopShift on the classic benchmark pocket T4 Lysozyme L99A. We find that PopShift is more accurate than common strategies, such as docking to a single structure and traditional ensemble docking─producing results that compare favorably with alchemical binding free energy calculations in terms of RMSE but not correlation─and may have a more favorable computational cost profile in some applications. In addition to predicting binding free energies and ligand poses, PopShift also provides insight into how the probability of different protein structures is shifted upon addition of various concentrations of ligand, providing a platform for predicting affinities and allosteric effects of ligand binding. Therefore, we expect PopShift will be valuable for hit finding and for providing insight into phenomena like allostery.

Alloplastic temporomandibular joint replacement - past, present, and future: "Learn from the past, prepare for the future, live in the present." Thomas S. Monson.

Based on evidence from the orthopaedic, biomedical engineering, and oral and maxillofacial surgical literature, this paper discusses reported successes and failures of past alloplastic temporomandibular joint (TMJ) devices that have led to the development of present total temporomandibular joint replacement (TMJR) devices. The paper concludes with discussion of the ongoing research that will lead to future embodiment (materials, designs, and manufacture) advances in TMJR management of severe and debilitating end-stage TMJ disease, further improving patients' mandibular function, form, and overall quality of life.

The Importance of Conducting Practice-oriented Research with Underserved Populations.

There has been a growing emphasis on dissemination of empirically supported treatments. Dissemination, however, should not be restricted to treatment. It can and, in the spirit of the scientific-practitioner model, should also involve research. Because it focuses on the investigation of clinical routine as it takes place in local settings and because it can involve the collaboration of several stakeholders, practice-oriented research (POR) can be viewed as an optimal research method to be disseminated. POR has the potential of addressing particularly relevant gaps of knowledge and action when implemented in regions of the world that have limited resources for or experiences with empirical research, and/or in clinical settings that are serving clinical populations who are not typically receiving optimal mental care services - specifically, individuals in rural and inner cities that have limited economic and social resources. The establishment and maintenance of POR in such regions and/or settings, however, come with specific obstacles and challenges. Integrating the experiences acquired from research conducted in various continents (Africa, Europe, Latin America, and North America), the goal of this paper is to describe some of these challenges, strategies that have been implemented to address them, as well as new possible directions to facilitate the creation and growth of POR. It also describes how these challenges and ways to deal with them can provide helpful lessons for already existing POR infrastructures.

Therapeutic techniques and session impact: A practice-research network study in private practice.

Objective: This study investigated the relationship between therapeutic techniques and session impact, by examining the replicability of findings observed in a university-based training clinic (Boswell et al., 2010) in another practice-oriented setting: private practice.Method: N = 8 therapists completed session-level assessments of their technique use for N = 38 clients. The same client sample completed session-level assessments of session outcome. Technique-outcome associations were examined with multilevel models.Results: As in Boswell et al., common factors were associated with positive session impact. For clients who received higher average common factor techniques (relative to their own therapist's caseload), session impact was the poorest in sessions with higher behavioral change techniques use (relative to the client's own average). Moreover, clients with the lowest average common factor techniques (relative to their therapist's caseload) reported better session impact in sessions that involved a higher degree of session-level behavioral change techniques (relative to their own average).Conclusion: In line with Boswell et al., therapists should be mindful of the consistency of their routine technique use between- and within-clients, and this can be aided through collection of their own practice-oriented data.